Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression

Pérez Lorite, Neus; Apostolova, Sonia; Guasch Vallés, Marta; Pryer, Aaron; Unzueta, Fernando; Freire, Raimundo; Solé-Soler, Roger; Pedraza González, Neus; Dolcet Roca, Xavier; Garí Marsol, Eloi; Agell, Neus; Taylor, Elaine M.; Colomina i Gabarrella, Neus; Torres Rosell, Jordi

Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression

The Smc5/6 complex is a highly conserved molecular machine involved in the maintenance of genome integrity. While its functions largely depend on restraining the fork remodeling activity of Mph1 in yeast, the presence of an analogous Smc5/6-FANCM regulation in humans remains unknown. We generated hu...

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Detalhes bibliográficos
Autores:	Pérez Lorite, Neus, Apostolova, Sonia, Guasch Vallés, Marta, Pryer, Aaron, Unzueta, Fernando, Freire, Raimundo, Solé-Soler, Roger, Pedraza González, Neus, Dolcet Roca, Xavier, Garí Marsol, Eloi, Agell, Neus, Taylor, Elaine M., Colomina i Gabarrella, Neus, Torres Rosell, Jordi
Tipo de documento:	artigo
Estado:	Versão publicada
Data de publicação:	2024
País:	España
Recursos:	Universitat de Lleida (UdL)
Repositório:	Repositori Obert UdL
OAI Identifier:	oai:repositori.udl.cat:10459.1/466302
Acesso em linha:	https://doi.org/10.1007/s00018-024-05275-3 https://hdl.handle.net/10459.1/466302
Access Level:	Acceso aberto
Palavra-chave:	DNA replication Genomic stability NSE1 Smc5/6 SMC5 SMC6 NSE2 NSE3 NSE4 FANCM RING DNA fiber MMS Anaphase Fanconi anemia

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spelling	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progressionPérez Lorite, NeusApostolova, SoniaGuasch Vallés, MartaPryer, AaronUnzueta, FernandoFreire, RaimundoSolé-Soler, RogerPedraza González, NeusDolcet Roca, XavierGarí Marsol, EloiAgell, NeusTaylor, Elaine M.Colomina i Gabarrella, NeusTorres Rosell, JordiDNA replicationGenomic stabilityNSE1Smc5/6SMC5SMC6NSE2NSE3NSE4FANCMRINGDNA fiberMMSAnaphaseFanconi anemiaThe Smc5/6 complex is a highly conserved molecular machine involved in the maintenance of genome integrity. While its functions largely depend on restraining the fork remodeling activity of Mph1 in yeast, the presence of an analogous Smc5/6-FANCM regulation in humans remains unknown. We generated human cell lines harboring mutations in the NSE1 subunit of the Smc5/6 complex. Point mutations or truncations in the RING domain of NSE1 result in drastically reduced Smc5/6 protein levels, with differential contribution of the two zinc-coordinating centers in the RING. In addition, nse1-RING mutant cells display cell growth defects, reduced replication fork rates, and increased genomic instability. Notably, our findings uncover a synthetic sick interaction between Smc5/6 and FANCM and show that Smc5/6 controls fork progression and chromosome disjunction in a FANCM-independent manner. Overall, our study demonstrates that the NSE1 RING domain plays vital roles in Smc5/6 complex stability and fork progression through pathways that are not evolutionary conserved.This work was supported by grants PGC2018-097796-B-I00 and PID2021-127689NB-I00 to JT-R, PID2019-109222RB-I00 and PID2022-139691OB-I00 to RF funded by MICIN/AEI/https://doi. org/10.13039/501100011033/ and European Union Regional Funds (FEDER); grant 2017-SGR-569 to EG funded by AGAUR-Generalitat de Catalunya; the IRBLLEIDA institute is part of the CERCA Programme/Generalitat de Catalunya. Work in EMT lab was supported by grant CR1190 from North West Cancer Research and by a Minor Medical Grant from The Dowager Countess Eleanor Peel Trust. NPL was supported by a “Formación de doctores” fellowship (FPI/ PRE2019-090744); SA by a UdL predoctoral fellowship and a Diputació de Lleida contract; MG by the INVESTIGO-AGAUR program funded by the European Union’s NextGenerationEU (NGEU) recovery plan; RS-S by a “Formación de Profesorado Universitario” fellowship (FPU16/07021) from the Spanish government. Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature.Springer2024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://doi.org/10.1007/s00018-024-05275-3https://hdl.handle.net/10459.1/466302reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)Inglés097796Reproducció del document publicat a: https://doi.org/10.1007/s00018-024-05275-3Cellular and Molecular Life Sciences, 2024, vol. 81, 251cc-by (c) authors, 2024Attribution 4.0 Internationalinfo:eu-repo/semantics/openAccesshttp://creativecommons.org/licenses/by/4.0/oai:repositori.udl.cat:10459.1/4663022026-06-24T12:42:17Z
dc.title.none.fl_str_mv	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression
title	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression
spellingShingle	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression Pérez Lorite, Neus DNA replication Genomic stability NSE1 Smc5/6 SMC5 SMC6 NSE2 NSE3 NSE4 FANCM RING DNA fiber MMS Anaphase Fanconi anemia
title_short	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression
title_full	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression
title_fullStr	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression
title_full_unstemmed	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression
title_sort	Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression
dc.creator.none.fl_str_mv	Pérez Lorite, Neus Apostolova, Sonia Guasch Vallés, Marta Pryer, Aaron Unzueta, Fernando Freire, Raimundo Solé-Soler, Roger Pedraza González, Neus Dolcet Roca, Xavier Garí Marsol, Eloi Agell, Neus Taylor, Elaine M. Colomina i Gabarrella, Neus Torres Rosell, Jordi
author	Pérez Lorite, Neus
author_facet	Pérez Lorite, Neus Apostolova, Sonia Guasch Vallés, Marta Pryer, Aaron Unzueta, Fernando Freire, Raimundo Solé-Soler, Roger Pedraza González, Neus Dolcet Roca, Xavier Garí Marsol, Eloi Agell, Neus Taylor, Elaine M. Colomina i Gabarrella, Neus Torres Rosell, Jordi
author_role	author
author2	Apostolova, Sonia Guasch Vallés, Marta Pryer, Aaron Unzueta, Fernando Freire, Raimundo Solé-Soler, Roger Pedraza González, Neus Dolcet Roca, Xavier Garí Marsol, Eloi Agell, Neus Taylor, Elaine M. Colomina i Gabarrella, Neus Torres Rosell, Jordi
author2_role	author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	DNA replication Genomic stability NSE1 Smc5/6 SMC5 SMC6 NSE2 NSE3 NSE4 FANCM RING DNA fiber MMS Anaphase Fanconi anemia
topic	DNA replication Genomic stability NSE1 Smc5/6 SMC5 SMC6 NSE2 NSE3 NSE4 FANCM RING DNA fiber MMS Anaphase Fanconi anemia
description	The Smc5/6 complex is a highly conserved molecular machine involved in the maintenance of genome integrity. While its functions largely depend on restraining the fork remodeling activity of Mph1 in yeast, the presence of an analogous Smc5/6-FANCM regulation in humans remains unknown. We generated human cell lines harboring mutations in the NSE1 subunit of the Smc5/6 complex. Point mutations or truncations in the RING domain of NSE1 result in drastically reduced Smc5/6 protein levels, with differential contribution of the two zinc-coordinating centers in the RING. In addition, nse1-RING mutant cells display cell growth defects, reduced replication fork rates, and increased genomic instability. Notably, our findings uncover a synthetic sick interaction between Smc5/6 and FANCM and show that Smc5/6 controls fork progression and chromosome disjunction in a FANCM-independent manner. Overall, our study demonstrates that the NSE1 RING domain plays vital roles in Smc5/6 complex stability and fork progression through pathways that are not evolutionary conserved.
publishDate	2024
dc.date.none.fl_str_mv	2024
dc.type.none.fl_str_mv	info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion
format	article
status_str	publishedVersion
dc.identifier.none.fl_str_mv	https://doi.org/10.1007/s00018-024-05275-3 https://hdl.handle.net/10459.1/466302
url	https://doi.org/10.1007/s00018-024-05275-3 https://hdl.handle.net/10459.1/466302
dc.language.none.fl_str_mv	Inglés
language_invalid_str_mv	Inglés
dc.relation.none.fl_str_mv	097796 Reproducció del document publicat a: https://doi.org/10.1007/s00018-024-05275-3 Cellular and Molecular Life Sciences, 2024, vol. 81, 251
dc.rights.none.fl_str_mv	cc-by (c) authors, 2024 Attribution 4.0 International info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/4.0/
rights_invalid_str_mv	cc-by (c) authors, 2024 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv	openAccess
dc.publisher.none.fl_str_mv	Springer
publisher.none.fl_str_mv	Springer
dc.source.none.fl_str_mv	reponame:Repositori Obert UdL instname:Universitat de Lleida (UdL)
instname_str	Universitat de Lleida (UdL)
reponame_str	Repositori Obert UdL
collection	Repositori Obert UdL
repository.name.fl_str_mv
repository.mail.fl_str_mv
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Crucial role of the NSE1 RING domain in Smc5/6 stability and FANCM-independent fork progression

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